of Genetics motor diseases
1. 2. 3. 4.
Multiple sclerosis (MS) Amyotrophic lateral sclerosis (ALS) Huntingtons disease Parkinsons disease
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Multiple Sclerosis: many scars
Population frequency: 1/1000 - 1/10,000 Age of onset: 20-40 yrs old Phenotype: loss of movements, muscle spasms, difficulty in coordination, wide variation Disease basis: Axon demyelination, axon degeneration
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MS is a progressive disease
85% relapsing/remitting initially 1-2 episodes/yr (2/3 become progressive after several years) 15% progressive 50% unable to perform household/employment responsibilities (10yrs) 50% unable to walk (25yrs)
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MS is caused by demyelination of axons
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Is this an immune disease or a neurodegenerative disease?
Disorders in MS:
Which comes first? Primary oligo degeneration leads to myelin breakdown, leads to secondary inflammation??? 5
Inhibiting the immune system slows MS
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Current MS treatments attack the immune system
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Amyotrophic lateral sclerosis (ALS)
no muscle nourishment, spinal cord scarring Population frequency: 1/100,000 Age of onset: 50-70 Phenotype: weakness, muscle wasting, no cure, fatal 2-5 yrs cant breathe Disease basis: 90% sporadic 10% familial 20% familial gene defect in superoxide dismutase
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Characteristics of ALS
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Superoxide Dismutase is a free radical scavenger
reduces oxidative stress converts O- to O2 or H2O2 cytoplasmic ALS is caused by a Gain-of-function SOD, not lof, dominant negative Misfolded protein??? Generates more free radicals??
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A mouse model for ALS: Can misexpress the human mutant in different cell-types Only in neurons, no disease Only in astrocytes, no disease 11
Which cells promote motor neuron degeneration in ALS?
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1. Generate ES cells from mice with human SOD mutant, form motor neurons What happens to MN survival?
2. Test the role of glia by co-culturing with WT glia or SOD mutant glia
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Huntingtons Disease
Population frequency: 5/100,000 Age of onset: 35-45 Phenotype: involuntary writhing movements (chorea), hyperkinesis decline in physical and mental abilities, death 20 yrs post-onset Disease basis: Genetic, Huntingtin protein
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Characteristics of Huntingtons Disease
18yrs old
30 yrs old
Charles Oscar Waters in 1841 provides a lucid picture of one of its main clinical features, chorea, and its hereditary nature [2]: It consists essentially in a spasmodic action of all the voluntary muscles of the system, of involuntary and more or less irregular motions of the extremities, face and trunk The disease is markedly hereditary The first indications of its appearance are spasmodic twitching of the extremities, generally of the fingers which gradually extend and involve all the involuntary muscles. This derangement of muscular action is by no means uniform; in some cases it exists to a greater, in others to a lesser, extent, but in all cases gradually induces a state of more or less perfect dementia. When speaking of the manifestly hereditary nature of the disease, I should perhaps have remarked that I have never known a case of it to occur in a patient, one or both of whose ancestors were not, within the third generation at farthest, the subject of this malady distressing
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Huntingtons Disease is autosomal dominant
Nancy Wexler Pedigree of HD in Argentinian family
Dr Negrette 1955 identified village on Lake Maracaibo, VZ With high HD frequency ~700/100,000 Wexler and colleagues collected a pedigree of 18000 individuals, 4000 blood samples,Tip chromosome 4 17
Cloning the gene (the beginning of large-scale DNA analyses)
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Used restriction fragment length polymorphisms, identified one on the tip of chromosome 4 that segregated with the disease 2.2 MB
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Isolated genomic DNA spanning the interval, used exon trapping To identify candidate genes IT15 (interesting transcript 15) 350kD novel protein, expanded CAG repeats in HD 18
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RFLP mapping: segregation of the marker with the mutant phenotype
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In the satirical masterpiece Catch-22 by Joseph Heller, Major Major Majors father makes a living by not growing alfalfa. In a moment of uncalled-for unkindness stimulated by alcohol, I once accused a close colleague of making a living by not cloning the HD gene. It is hardly surprising that he should have retaliated by sending me a preprint of the article in this issue. It was disappointing that it took such a long time to go from linkage to gene cloning, but it proved to be a complex problem. In the end, all of the skills of the 58 coworkers in the Huntington s Disease Collaborative Research Group and those of many others were needed.
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Huntingtin and its normal cellular roles Huntingtin and
Biochemical Journal
www. biochemj.org
Biochem. J. (2008) 412, 191-209
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Expanded CAG repeats are a hallmark of HD
Several other diseases caused by trinucleotide expansions
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Parkinsons Disease
Population frequency: 3/1000 (1-2% >60) Age of onset: 50-70 Phenotype: resting tremors, posture/muscle tone, shuffling gait, slowness Disease basis: Degeneration of DOPA neurons in the substantia niagra
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Depletion of DOPA causes paralysis, rescued by DL-DOPA injection
Reserpine is a MAO transporter inhibitor 24
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Key findings implicating DOPA in Parkinsons Disease
Treatment of reserpine resembles Parkinsons Disease Dopamine depleted in Parkinsons brains Provide DOPA rescue Parkinsons Disease (with caveats)
Discoveries in the 1960s, Nobel prize 2000
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DOPA acts on the motor system
Basal ganglia and cerebellum Reciprocally connect with M1
Substantia niagra and striatum are basal nuclei
DOPA activates a direct pathway that facilitates movement; increases thalamic input to M1 26
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Other drugs that mimic Parkinsons
1. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin) Synthetic opiate MPPP MPTP contaminant found in a batch of MPPP Caused 6 people to exhibit Parkinsons pheontype 3 days after taking Selectively toxic to Sustantia Niagra neurons (DOPA)
glia
neuron 27
MPTP-induced Parkinsons rescued by L-DOPA
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Other drugs that mimic Parkinsons
Rotenone 2. Paraquat, an widely used herbicide, causes PD in animal models banned in EU, restricted use in US
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Many genes have been associated with Parkinsons Disease
PARK1 - PARK 13 only 5-10% of all Parkinsons patients have a mutation in 1 of the 13 genes PARK1 = SYN1 = vesicle priming PARK2 = PARKIN = ubiquitin ligase 30
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